Objective: To determine whether gut dysbiosis alone is sufficient to induce Parkinson’s disease (PD) pathology and to investigate its impact on host metabolism.

Background: Gut microbiota dysbiosis has been implicated in PD progression, but its role in disease initiation remains unclear. While previous studies have shown microbial composition shifts in PD patients, the causative relationship between dysbiosis and neurodegeneration is not well established.

Method: Fecal microbiota from 18-month-old VPS35D620N/+ knockin mice, a model of PD-associated dysbiosis, were transplanted into germ-free C57BL/6J mice. Motor function was assessed via rotarod and grip strength tests, and dopaminergic neuron integrity was evaluated using tyrosine hydroxylase (TH) immunostaining in the substantia nigra pars compacta (SNpc). Microbiome composition and host metabolic changes were analyzed through 16S rRNA sequencing and targeted metabolomics.

Results: Transplantation of dysbiotic microbiota did not lead to significant reductions in TH-positive neurons or motor function impairment, indicating that gut dysbiosis alone does not induce PD-like neurodegeneration. However, microbiome analysis revealed marked alterations in microbial composition and metabolic pathways, including decreased levels of short-chain fatty acids (SCFAs) and tryptophan metabolites in serum. These changes suggest that dysbiosis contributes to a pre-inflammatory and nutrient-deficient state, potentially increasing susceptibility to neurodegenerative stressors.

Conclusion: While dysbiosis alone does not trigger PD pathology, its impact on host metabolism suggests a role as a disease-modifying factor. The observed metabolic disruptions, particularly in SCFA and tryptophan metabolism, highlight potential targets for therapeutic intervention. Future studies should explore how dysbiosis interacts with additional PD risk factors to influence disease onset and progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gut-dysbiosis-alters-host-metabolism-but-does-not-independently-induce-parkinsons-disease-pathology/